NSC23766 is identified to fit into a surface groove of Rac1 known to be critical for GEF specification. NSC23766 effectively inhibits Rac1 binding and activation by the Rac-specific GEF Trio or Tiam1 in a dose-dependent manner without interfering with the closely related Cdc42 or RhoA binding or activation by their respective GEFs or with Rac1 interaction with BcrGAP or effector PAK1. NSC 23766 is active in regulating Rac GTPase functions on cytoskeleton and many cell functions including cell cycle, cell growth, adhesion, migration and gene transcription. NSC 23766 (50 μM) potently blocks serum or platelet-derived growth factor-induced Rac1 activation and lamellipodia formation without affecting the activity of endogenous Cdc42 or RhoA in NIH 3T3 cells. NSC 23766 reduces Trio or Tiam1 but not Vav, Lbc, Intersectin, or a constitutively active Rac1 mutant-stimulated NIH 3T3 cells growth and suppresses Trio, Tiam1, or Ras-induced cell transformation. NSC23766 dose-dependently inhibits PC-3 cells proliferation and anchorage-independent growth. 25 μM NSC23766 inhibits the PC-3 cell invasion through Matrigel by 85%.  50 μM NSC 23766 inhibits thrombin-induced activation of Rac1 an d Rac2 in human platelets, as well as platelet aggregation. NSC23766 prevents Aβ40 and Aβ42 production in swAPP-HEK293cells without affecting Notch and sAPPα. NSC23766 prevents γ-secretase activity in cell, but not act as a direct γ-secretase inhibitor. NSC23766 dose-dependently reduces levels of secreted and intracellular Aβ40 with IC50 of 48.94 μM. 50 μM NSC 23766 inhibits release of Aβ42 by 57.97%. NSC23766 regulates endothelial nitric oxide synthase expression and endothelial function. 100 μM NSC23766 represses the eNOS promoter activity by 60% in bovine aortic ECs and by 30% to 35% in bEND.3 cells. Inhibition of Rac1 with NSC23766 destabilizes eNOS mRNA and shortens its half-life to 17 hours. NSC23766 dose-dependently attenuates ACh-induced relaxation of wild-type mice aortic rings.
|Cell lines||Human breast cancer cells MDA-MB-468|
|Preparation method||Cells (1.5 × 10^4/mL) are seeded in each well of 96-well tissue culture plates with 200 μL of medium. After 24 hours of plating, the medium is replaced with 200 μL of fresh medium containing NSC23766 at the indicated concentrations. At the end of the treatment period 20 μL of MTS solution are added to each well and incubated at 37 ℃ for 2 hours. Absorbance at 490 nm is read on a 96-well plate reader.|
|Incubation time||2 days|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
|Solubility||DMSO 10 mM|
The Role of Rac1 on Carbachol-induced Contractile Activity in Detrusor Smooth Muscle from Streptozotocin-induced Diabetic Rats.
Evcim AS, et al. Basic Clin Pharmacol Toxicol. 2015 Jun;116(6):476-84. PMID: 25382267.
Tiam1/Rac1 signals contribute to the proliferation and chemoresistance, but not motility, of chronic lymphocytic leukemia cells.
Hofbauer SW, et al. Blood. 2014 Apr 3;123(14):2181-8. PMID: 24501217.
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